Irritable Bowel Syndrome (IBS) is a common chronic gastrointestinal (GI) disorder characterized by symptoms of abdominal pain or discomfort associated with disturbed defecation. Patients with IBS suffer from a high degree of psychiatric comorbidity, in particular depression, anxiety, and posttraumatic stress disorder. We hypothesize that the frequent psychiatric comorbidity in IBS points to a common etiological factor, a disruption in serotonergic signaling affecting both the gut and the brain. The major regulator of serotonergic neurotransmission in the body is the serotonin transporter (SERT). SERT controls the intensity and duration of serotonergic signaling via re-uptake of serotonin into the synapse and is therefore a candidate gene for IBS. Our previous studies have shown that there is a subgroup of IBS patients with a particularly severe form of the disease who are more likely to suffer from psychiatric comorbidity, particularly depression. We therefore formulate the hypothesis that there is a subgroup of adults with deleterious mutations of SERT that (a) suffer from a high GI symptom burden in IBS, (b) have high rates of psychological distress, and (c) have a poor response to all forms of IBS treatment. In this study we will sequence the coding and non-coding regions of the SERT gene in 373 patients with IBS and 137 controls, using the ABI SOLiD platform. We will identify rare coding and non-coding SERT sequence variants (SERT mutations) and characterize their functional importance, using bioinformatics tools. The aims of the study are: Aim 1: Compare the prevalence of deleterious SERT mutations in 373 patients with IBS to 137 healthy controls. Aim 2: Compare IBS patients with and without deleterious SERT mutations with respect to GI symptoms and symptoms of psychological distress. Aim 3: Compare response to cognitive-behavioral treatment in IBS patients with and without deleterious SERT mutations. PUBLIC HEALTH RELEVANCE: Irritable bowel syndrome (IBS) is a common and painful gastrointestinal disease of unknown etiology, often accompanied by depression, anxiety, or posttraumatic stress disorder. Evidence points towards a global dysfunction of serotonin signaling as possible cause for this combination of gastrointestinal and psychiatric symptoms. The goal of this study is to test the hypothesis that harmful mutations of the serotonin transporter gene can cause IBS.